Submissions for variant NM_000051.4(ATM):c.2927T>C (p.Val976Ala)

gnomAD frequency: 0.00014  dbSNP: rs146145357

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166813	SCV000217627	likely benign	Hereditary cancer-predisposing syndrome	2018-04-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230218	SCV000282916	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 976 of the ATM protein (p.Val976Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with acute myeloid leukemia and breast cancer (PMID: 26689913, 28503720). ClinVar contains an entry for this variant (Variation ID: 187123). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000588819	SCV000293347	uncertain significance	not provided	2021-11-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with acute myelogenous leukemia, breast cancer, or renal cancer (Lu 2015, Rummel 2017, Yehia 2018); This variant is associated with the following publications: (PMID: 23555315, 28503720, 26689913, 29684080)
Color Diagnostics, LLC DBA Color Health	RCV000166813	SCV000682090	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 976 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 28503720) and in an individual affected with acute myeloid leukemia (PMID: 26689913). This variant has also been identified in 9/246048 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271439	SCV000694239	uncertain significance	not specified	2022-06-09	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2927T>C (p.Val976Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251230 control chromosomes, predominantly at a frequency of 0.00055 (9/16230) within the African or African-American subpopulation in the gnomAD database. It has also been observed at a frequency of 0.001172 (3/2559) within African Americans in women over seventy with no history of cancer (FLOSSIES database). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2927T>C has been reported in the literature in individuals affected with breast cancer and acute myeloid leukemia, without strong evidence for causality (example Haiman_2013, Lu_2015, Rummel_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Six laboratories classified the variant as VUS, and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000230218	SCV000799924	uncertain significance	Ataxia-telangiectasia syndrome	2018-05-14	criteria provided, single submitter	clinical testing
Mendelics	RCV003491911	SCV000838513	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000588819	SCV001879413	uncertain significance	not provided	2021-06-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462227	SCV004205113	uncertain significance	Familial cancer of breast	2024-03-19	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003462227	SCV005083541	likely benign	Familial cancer of breast	2024-05-10	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].